In sub-Saharan Africa, children carry a large proportion of the overall burden of tuberculosis (TB) and HIV co-infection. The management of TB in HIV-infected children presents major challenges and unresolved issues, including diagnostic difficulties of paucibacillary disease, timing of initiation of antiretroviral (ARV) drugs, drug-drug interactions, overlapping drug toxicities, and the occurrence of the immune reconstitution inflammatory syndrome (IRIS). The management of TB/HIV co-infection in young children is further complicated by the limited choice of ARVs and high rates of malnutrition. Our understanding of the incidence, immunopathogenesis and public health importance of pediatric TB-IRIS is limited to a few small studies. Evidence-based guidelines for concomitant treatment of TB and HIV in children are lacking, and little pharmacokinetic information is available on the interaction of first line ARV and TB drugs in children. We propose to estimate the incidence of TB-IRIS in a cohort of 672 children initiating ARV in Johannesburg, South Africa, measure the association of IRIS with malnutrition, and unravel the immunopathogenesis of pediatric TB-IRIS. We will screen children with prevalent TB at time of ARV initiation for the development of paradoxical TB-IRIS, and children free of TB at baseline will be prospectively assessed for incident or unmasking TB-IRIS during the first 6 months of ARV treatment. A nested case-control study will be performed to unravel the immunopathogenesis of TB-IRIS, with a focus on cytokine expression measurements, lymphocyte subset immunophenotyping and assessment of the role of regulatory T cells. To improve the diagnosis of TB-IRIS, we propose to prospectively evaluate the predictive and diagnostic value of QuantiFERON. Gold in-tube, an FDA approved interferon gamma release assay. Specifically, we will measure interferon gamma production in all 672 children at baseline and 2 weeks after start ARV, and in all IRIS cases and their controls at time of enrollment in the nested case-control study. Finally, we propose to assess dosing, safety and pharmacokinetic profile of rifabutin, a rifamycin used in adults in the United States to overcome drug-drug interactions, when given concomitantly with LPV/RTV in young children (age <3 years). The results of the proposed research have the potential to substantially improve the management of HIV-infected children at risk of developing active TB or in need of concomitant TB/HIV treatment. In resource poor settings, children carry a large proportion of the burden of tuberculosis (TB) and HIV infection. The management of TB in HIV-infected children presents major challenges and unresolved issues. We will follow 672 children initiating HIV treatment in a clinic in Johannesburg South Africa to study TB-IRIS, a complication of TB and HIV co-infection. In these children, we will also study the use of rifabutin, a drug used in U.S. adults with TB and HIV. The results of the research have the potential to substantially improve the management of children with TB and HIV.